Isatine derivatives

Thiosemicarba2ones have long been used as antiviral agents, principally against pox vimses of the vaccinia family. One compound of this series, the isatin derivative (6) C HgN OS, has been used prophylacticaHy to prevent outbreaks of smallpox in humans (10) and to inhibit the protein synthesis in poxvims-infected cells. The molecular mechanics relating to this property are still not known (11), though the binding of a metal ion may be a key factor... 

Reaction of o-toluidine with chloral hydrate in presence of hydroxylamine hydrochloride and subsequent treatment with H2SO4 gave the isatin derivative 337. Bromination of 337 followed by reaction with sodium diethyl malonate gave 338. Catalytic reduction with Pd/C gave the oxoindole derivative 339 that upon hydrolysis with aqueous NaOH followed by... 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

Isatin derivatives and proline react to give stereospecific formation of an azo-methine ylide intermediate via the decarboxylation route. The resulting 1,3-dipole undergoes a cycloaddition reaction with N-substituted maleimide (6), as a dipolaro-... 

Reaction of isatin derivatives with 2,3-diaminoquinazoline in ethanolic KOH gave indolotriazinoquinazolinones 359 and triazinoquinazolinedi-ones 360, probably through a Schiff base intermediate. Such compounds showed a significant antibacterial activity [92IJC(B)105]. 

Azizian, Mehrdad, and co-workers reported a novel route to quinazolinones 123 through a Baeyer-Villiger pathway starting from isatin derivatives 120 <00TL5265>. The initial... 

The enantioselective hydrogenation of isatine derivatives has also been performed with high ee-values (up to 94%) using the alkyl-substituted oxoProNOP ligands (15 j). 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. The oxidation has been applied to alkyl 8"10 11 23 33>38-40>46 49>50>118halo n.18.35.36-38-40.47.10 .11 . 119,136,240 alkoxy,26,a8 39,47,75.io7,ii8,i36 trifluoromethyl,33,38,137 and nitro8,120,217 isatins. Use of N-substituted isatins led to N-substituted anthranilic acids.66,71,125,158,169,243 In the oxidation of 5-bromo-l-(y-carbethoxypropyl)-7-ethylisatin, 60 was isolated after treatment with ethanol and acid.11 Oxidation of isatin derivatives 61 led, after treatment with diazomethane, to the acridine derivatives 62.67 Application of this oxidation method to 7-hydroxyisatins gave rise to benzoxazo-lones (63).2,41... 

Piperidinomethylisatin on lithium aluminum hydride gave the indoline 67 while sodium borohydride reduction of the same isatin derivative gave a reductive dimerization to 68 and a reduction-rearrangement to 69.255... 

A number of cyclization reactions have been carried out with isatin derivatives of this series. Isatin-3-thiosemicarbazone with chloroacetic acid, sodium acetate, acetic acid, and aldehydes gave 107.392,393... 

The cyclization of certain 2-substituted isatin derivatives were studied so as to compare them with the above cyclizations. Thus, isatin- 2-thiosemicarbazone (126) and isatin-2-semicarbazone (127) underwent cyclization to 128 and 129 more easily than the corresponding cyclizations in the 3-series.406 As in the 3-series the sulfur compound underwent cyclization more easily than the oxygen.408 In contrast to... 

The azepane (3)-3-methyl-l- 3-oxo-l-[2-(3-pyridin-2-ylphenyl)ethenoyl]azepane 4-ylcarbamoyl butylamide is a potent nonpeptide inhibitor of rat cathepsin K (and thus of potential value in the control of osteoclast-mediated bone resorption) <2002MI746>, and an N-substituted azepane-isatin derivative was reported to be a nonpeptide inhibitor of caspase 3 <2001JME2015> another N-substituted azepane-indole derivative was shown to act as an estrogen <2001JME1654>. 

The Menshutkin acid chloride was used by the author of [19] for the cyclization of isatin derivatives, and l-[(perhydro-2-alkoxy-l,3,6,2-dioxaazophosphocin-6-yl)methyl]isatins (53) were obtained ... 

Keywords isatin, isatin derivatives, ketones, 4-quinolinecarboxylic acid derivatives, condensation, cyclization, Pfitzinger reaction, recyclization. 

In conclusion it is necessary to mention papers in which the recyclization of isatin derivatives 222 and 223 to 4-cinnolinecarboxylic [186-188] or 4-quinazolinecarboxylic [189] acids 224, 225, and 226 was studied. These transformations are presented in the schemes below. 

Isatine derivatives gave the corresponding cycloadducts with high stereoselectivity when irradiated in the presence of furan and benzofuran [72]. The reaction of furan with acyl cyanides yields the corresponding oxetanes, but both diastereoisomeric endo- and exo-oxetanes are formed (Scheme 3.36). When chiral acyl cyanides are used, low asymmetric induction is observed [73]. Furan also reacts with chiral ketones. In this case, an ot-cleavage reaction before the 2+2 cycloaddition modifies the expected products (Scheme 3.37). When (—)-menthone was used as a substrate, a chiral product was obtained as a 2 1 diastereoisomeric mixture the most abundant product has the (1/ , 3R) configuration [74]. When the reaction was performed on carbohydrate 36, a complex reaction mixture was obtained (Scheme 3.38) [74, 75]. 

Photoinduced [2+2] cycloaddition (the Paterno-Buchi reaction) of 1-acetylisatin with acyclic enol ethers afford the spiro(3f/-indole-3,2 -oxetane)s 43 with moderate regio- and diastereoselectivity via the mi triplet state of the isatin derivative without involvement of single electron transfer <02JCS(P1)345>. 

Details of the structure elucidation of melosatins A (4) and B (5)10 have now been published 110 melosatin C, a new metabolite from Melochia tomentosa L., is the closely related 4-(5-phenylpentyl)isatin derivative (6). 

This method has been used for the synthesis of 1-aryl and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine as well as indoline. In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A, albeit in very low yield (Scheme 8). 

Many methods have been devised for the /V-alkylation of isatins. These derivatives are commonly synthesized from the reaction of the sodium salt of isatin with alkyl halides or sulphates . Various methods for the preparation of this salt have been reported, and include the reaction of isatin with sodium hydride, either in toluene under reflux74 or in DMF75. Other methods include the use of potassium carbonate in DMF76,77 or in acetone78. In the latter case an aldol reaction of the solvent also occurs with the C-3 carbonyl of the isatin derivative. 

The Mannich reaction is readily applied to isatins. The products of this reaction, the N-aminomethylisatins (Mannich bases), can also be obtained from the A -hydroxymethyl derivatives by reaction with an amine95 or by reaction with acetyl chloride to yield N-chloromethylisatin which can be further treated with potassium phthalimide or alcohols to give the corresponding A-phthalimidomethyl or TV-alkoxymethyl isatins96. The Mannich reaction can also be performed with isatin derivatives, such as isatin-3-hydrazones97 and isatin-3-thiosemicarbazones98. 

The reactions of some isatin derivatives with organometallic reagents follow reaction patterns that differ from those of isatin. Addition of phenylmagnesium bromide to isatin-3-acylhydrazones gave a product resulting from nucleophilic attack at C-2442 (Scheme 103). 

Isatinates, obtained from the alkaline hydrolysis of isatin derivatives, are the precursors of the quinoline-4-carboxylic acids. These compounds are prepared by the Pfitzinger reaction from isatins in the presence of enolizable keto compounds in strongly alkaline medium, such as 8N KOH. In these solutions, isatinates condense with the keto compound and subsequently cyclize to the quinoline products. Recently, a modified procedure has been described, using acidic conditions. This methodology was subsequently applied to a concise manner for the preparation of derivatives of camptothecin, a topoisomerase I inhibitor23 (Scheme 115). 

The lithium and thallium (I) salts of i satin-3-oxime (isatin oximates) were employed in the development of ion-selective electrodes for these cations. Transition metal complexes of isatin derivatives can also be employed as catalysts for the oxidative self-coupling of alkylphenol s639,640. 

Amines and hydroxylamine and hydrazine derivatives react with 36 at the lactim ether group and not at the keto group76 88 [Eq. (2)]. By contrast, in the reaction between the imidochloride of isatin and tosylhydrazine (or aniline) the keto group at position 3 was found to be attacked and at the same time the imidochloride was transformed into the lactam89 [Eq. (3)]. Thus it may be argued that, at least in the case of the isatin derivatives, the lactim ether function is more reactive than the imidochloride. 

A theoretical determination of vibrational absorption and Raman spectra of 3-methylindole radicals has been carried out in comparison to experimentally measured spectra for 3-methylindole (Table 28) to provide specific spectroscopic markers for the detection of neutral or cationic tryptophan radicals in biological systems <2001CPH(265)13>. Among isatin derivatives, substitution at C-5 has relatively greater influence on the electron density and the force constant of the amide than of the ketone carbonyl group (Table 29) <2001SAA469>. 

The ring closure to an isatin derivative takes place only under certain, accurately controlled conditions. It is important that the reaction be carried out in hot sulfuric acid. 

Isatin (lH-indole-2,3-dione) is an endogenous compoimd identified in humans. This class of compoimds possesses a wide range of biological activities [35] that include antiallergic, anticancer, anticonvulsant, antidiuretic, antithrombotic, antitubercular, antiviral, anxiogenic, immunosuppressant, muscle relaxant, and sedative activities. Vine et aL [36] synthesized a variety of isatin derivatives (XII) and evaluated their cytotoxic activities against the human monocyte-Uke histiocytic lymphoma (U937) ceU line in vitro. We used these cytotoxic data to develop QSAR Eq. 11 (Table 5) ... 

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